p38α MAP kinase (MAPK) is an intracellular serine/threonine kinase involved in the regulation of inflammatory cell signals and plays a central role in the regulation of pro-inflammatory cytokine production. Activation of p38α is produced by upstream kinases MKK6 and MKK3. At molecular level, like other protein kinases, p38α is responsible for the transfer of the γ-phosphate form ATP to a range of substrate proteins including the transcription factors ATF2, Elk-1 and MEF2A and downstream kinases like MK2, MK3, PRAK, MNK1/2 and MSK1, modulating their function (Stokoe et al., 1992, EMBO J. 11, 3985-3994).
p38α has been identified as a potential target for anti-inflammatory drugs, and different binding sites for these drugs have been identified (Akella et al., January 2008, Biochim Biophys Acta; 1784(1): 48-55). Yong et al. review different p38 MAPK inhibitors which are under development as potential drugs for the treatment of inflammatory diseases and cancer (Yong et al., 2009, Expert Opin. Investig. Drugs; 18(12)). The majority of the drug candidates have proved to be competitive with ATP, binding to the active site. A few inhibitors have also been found that bind to a site adjacent to the active site. Akella et al. discuss the potential relevance of other binding sites such as the binding sites for D-motifs, FXFP and the Backside site.
Recently, evidences from both clinical studies and preclinical animal models have implicated overproduction of proinflammatory cytokines as a contributor to pathophysiology progression in chronic neurodegenerative disorders like Alzheimer's disease, Parkinson's disease and multiple sclerosis (e.g. A. D. Bachstetter et al., Ageing and Disease 2010, Vol. 1, No. 3, pp. 199-211). This indicates that p38 MAPK signalling pathways could be viable targets for modulating inflammatory responses in neurological diseases.
Other MAP kinase that is also an important pharmaceutical target in the treatment of degenerative diseases of nervous system is the JNK MAP kinase. JNK MAP kinase provides key signals in the brain for both neuronal apoptosis and amyloidigenic processing of APP, the two most important characteristics of Alzheimer's disease.
Despite several p38 MAPK inhibitors have been reported, they are currently no studies on use of p38 and JNK MAPK inhibitors for the treatment of degenerative diseases of nervous system or not even information available on whether any of such compounds are capable of passing through the blood-brain barrier.